Information regarding alpha adrenergic receptors, agonists and antagonists, in general, and regarding compounds related in structure to those of the subject invention are disclosed in the following references: Timmermans, P.B.M.W.M., A. T. Chiu & M.J.M.C. Thoolen, "12.1 .alpha.-Adrenergic Receptors", Comprehensive Medicinal Chemistry, Vol. 3, Membranes & Receptors, P. G. Sammes & J. B. Taylor, eds., Pergamon Press (1990), pp. 133-185; Timmermans, P.B.M.W.M. & P. A. van Zwieten," .alpha.-Adrenoceptor Agonists and Antagonists", Drugs of the Future, Vol. 9, No. 1, (January, 1984), pp. 41-55; Megens, A.A.H.P., J. E. Leysen, F. H. L. Awouters & C. J. E. Niemegeers, "Further Validation of in vivo and in vitro Pharmacological Procedures for Assessing the .alpha..sub.1 and .alpha..sub.2 -Selectivity of Test Compounds: (2) .alpha.-Adrenoceptor Agonists", European Journal of Pharmacology, Vol. 129 (1986), pp. 57-64; Timmermans, P.B.M.W.M., A. de Jonge, M.J.M.C. Thoolen, B. Wilfred, H. Batink & P. A. van Zwieten, "Quantitative Relationships between .alpha.-Adrenergic Activity and Binding Affinity of .alpha.-Adrenoceptor Agonists and Antagonists", Journal of Medicinal Chemistry, Vol. 27 (1984) pp. 495-503; van Meel, J. C. A., A. de Jonge, P.B.M.W.M. Timmermans & P. A. van Zwieten, "Selectivity of Some Alpha Adrenoceptor Agonists for Peripheral Alpha-1 and Alpha-2 Adrenoceptors in the Normotensive Rat", The Journal of Pharmacology and Experimental Therapeutics, Vol. 219, No. 3 (1981), pp. 760-767; Chapleo, C. B., J. C. Doxey, P. L. Myers, M. Myers, C. F. C. Smith & M. R. Stillings, "Effect of 1,4-Dioxanyl Substitution on the Adrenergic Activity of Some Standard .alpha.-Adrenoreceptor Agents", European Journal of Medicinal Chemistry, Vol. 24 (1989), pp. 619-622; Chapleo, C. B., R. C. M. Butler, D. C. England, P. L. Myers, A. G. Roach, C. F. C. Smith, M. R. Stillings & I. F. Tulloch, "Heteroaromatic Analogues of the .alpha..sub.2 -Adrenoreceptor Partial Agonist Clondine", J. Med. Chem., Vol. 32 (1989), pp. 1627-1630; Clare, K. A., M. C. Scrutton & N. T. Thompson, "Effects of .alpha..sub.2 -Adrenoceptor Agonists and of Related Compounds on Aggregation of, and on Adenylate Cyclase Activity in, Human Platelets", Br. J. Pharmac., Vol. 82 (1984), pp. 467-476; U.S. Pat. No. 3,890,319 issued to Danielewicz, Snarey & Thomas on Jun. 17, 1975; and U.S. Pat. No. 5,091,528 issued to Gluchowski on Feb. 25, 1992. However, many compounds related in structure to those of the subject invention do not provide the activity and specificity desirable when treating respiratory, ocular or gastrointestinal disorders.
It is particularly relevant to the subject invention that compounds found to be effective nasal decongestants are frequently found to have undesirable side effects, such as causing hypertension and insomnia, particularly when administered systemically. There is a need for new drugs which provide relief from nasal congestion without causing these undesirable side effects.
It is an object of the subject invention to provide novel compounds having substantial activity in preventing or treating nasal congestion.
It is a further object of the subject invention to provide such compounds which do not cause hypotension, drowsiness, hypertension, insomnia or other undesirable side effects, particularly when administered systemically.
It is also an object of the subject invention to provide novel compounds for treating cough, chronic obstructive pulmonary disease (COPD) and/or asthma.
It is also an object of the subject invention to provide novel compounds for treating glaucoma and/or diarrhea.
It is a still further object of the subject invention to provide such compounds which have good activity from peroral and/or topical and/or intranasal dosing.
It is an object of the subject invention to provide such novel compounds in pharmaceutically acceptable compositions.
It is an object of the subject invention to provide such novel compounds in pharmaceutically acceptable compositions in combinations with other active which provide further theraputic benefit.